A Phase III Randomised Study to Evaluate Dato-DXd and Durvalumab for Neoadjuvant/Adjuvant Treatment of Triple-Negative or Hormone Receptor-low/HER2-negative Breast Cancer

Sponsor

AstraZeneca (Industry)

Overall Status

Not yet recruiting

CT.gov ID

NCT06112379

Collaborator

Daiichi Sankyo, Inc. (Industry)

1,728

Enrollment

143

Locations

Arms

Anticipated Duration (Months)

12.1

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a Phase III, 2-arm, randomised, open-label, multicentre, global study assessing the efficacy and safety of neoadjuvant Dato-DXd plus durvalumab followed by adjuvant durvalumab with or without chemotherapy compared with neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab with or without chemotherapy in participants with previously untreated TNBC or hormone receptor-low/HER2-negative breast cancer.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: Dato-DXd Drug: Durvalumab Drug: Pembrolizumab Drug: Doxorubicin Drug: Epirubicin Drug: Cyclophosphamide Drug: Paclitaxel Drug: Carboplatin Drug: Capecitabine Drug: Olaparib	Phase 3

Detailed Description

The primary objectives of the study are to demonstrate superiority of neoadjuvant Dato-DXd plus durvalumab followed by adjuvant durvalumab with or without chemotherapy relative to neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab with or without chemotherapy in participants with previously untreated TNBC or hormone receptor low/HER2-negative breast cancer, by central assessment of pCR and/or to demonstrate superiority of neoadjuvant Dato-DXd plus durvalumab followed by adjuvant durvalumab with or without chemotherapy relative to neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab with or without chemotherapy in participants with previously untreated TNBC or hormone receptor-low/HER2-negative breast cancer, by investigator assessment of EFS

Study Design

Study Type:

Interventional

Anticipated Enrollment :

1728 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Participants will be randomised in a 1:1 ratio to one of two intervention groups.Participants will be randomised in a 1:1 ratio to one of two intervention groups.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase III, Open-label, Randomised Study of Neoadjuvant Datopotamab Deruxtecan (Dato-DXd) Plus Durvalumab Followed by Adjuvant Durvalumab With or Without Chemotherapy Versus Neoadjuvant Pembrolizumab Plus Chemotherapy Followed by Adjuvant Pembrolizumab With or Without Chemotherapy for the Treatment of Adult Patients With Previously Untreated Triple-Negative or Hormone Receptor-low/HER2-negative Breast Cancer (D926QC00001; TROPION-Breast04)

Anticipated Study Start Date :

Nov 15, 2023

Anticipated Primary Completion Date :

Mar 15, 2028

Anticipated Study Completion Date :

Aug 15, 2030

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dato-DXd plus durvalumab Participants receive durvalumab every 3 weeks (Q3W) + Dato-DXd Q3W as neoadjuvant therapy prior to surgery; followed by 9 cycles of durvaluamb Q3W as adjuvant therapy post-surgery. Adjuvant chemotherapy may be given in combination with durvalumab only if participants have residual disease. Olaparib may be given for participants with gBRCA-positive tumours and residual disease Adjuvant chemotherapy may be one of these: Doxorubicin (Q3W) or epirubicin (Q3W) + cyclophosphamide (Q3W) for 4 cycles (12 weeks) followed by paclitaxel (weekly) and carboplatin (weekly or Q3W) for 4 cycles (12 weeks); Doxorubicin (Q3W) or epirubicin (Q3W) + cyclophosphamide (Q3W) for 4 cycles (12 weeks) followed by paclitaxel (weekly) for 4 cycles (12 weeks); Carboplatin (weekly or Q3W) + paclitaxel (weekly) for 4 cycles (12 weeks); Capecitabine (Q3W) for 8 cycles.	Drug: Dato-DXd Experimental drug IV infusion Other Names: Datopotamab deruxtecan (Dato-DXd, DS-1062a) Drug: Durvalumab Experimental drug IV Infusion Other Names: MEDI4736 Drug: Doxorubicin IV infusion Experimental/Active Comparator Drug: Epirubicin IV Infusion Experimental/Active Comparator Drug: Cyclophosphamide IV infusion Experimental/Active Comparator Drug: Paclitaxel IV infusion Experimental/Active Comparator Drug: Carboplatin IV infusion Experimental/Active Comparator Drug: Capecitabine Tablet Oral route of administration Experimental/Active Comparator Other Names: XELODA®, Capecitabine Cell Pharm, Capecitabine EG, Capecitabine Accord Drug: Olaparib Tablet Oral route of administration Experimental/Active Comparator Other Names: LYNPARZA®
Active Comparator: Pembrolizumab plus chemotherapy Participants receive pembrolizumab every 3 weeks (Q3W) + paclitaxel weekly + carboplatin (weekly or Q3W) x 4 cycles, followed by pembrolizumab Q3W + (doxorubicin OR epirubicin) + cyclophosphamide Q3W x 4 cycles as neoadjuvant therapy prior to surgery; followed by 9 cycles of pembrolizumab Q3W as adjuvant therapy post-surgery. Adjuvant capecitabine (Q3W) for 8 cycles may be given in combination with pembrolizumab only if participants have residual disease. Olaparib may be given for participants with gBRCA-positive tumours and residual disease.	Drug: Pembrolizumab IV Infusion Active comparator Other Names: KEYTRUDA® Drug: Doxorubicin IV infusion Experimental/Active Comparator Drug: Epirubicin IV Infusion Experimental/Active Comparator Drug: Cyclophosphamide IV infusion Experimental/Active Comparator Drug: Paclitaxel IV infusion Experimental/Active Comparator Drug: Carboplatin IV infusion Experimental/Active Comparator Drug: Capecitabine Tablet Oral route of administration Experimental/Active Comparator Other Names: XELODA®, Capecitabine Cell Pharm, Capecitabine EG, Capecitabine Accord Drug: Olaparib Tablet Oral route of administration Experimental/Active Comparator Other Names: LYNPARZA®

Arm

Intervention/Treatment

Experimental: Dato-DXd plus durvalumab

Participants receive durvalumab every 3 weeks (Q3W) + Dato-DXd Q3W as neoadjuvant therapy prior to surgery; followed by 9 cycles of durvaluamb Q3W as adjuvant therapy post-surgery. Adjuvant chemotherapy may be given in combination with durvalumab only if participants have residual disease. Olaparib may be given for participants with gBRCA-positive tumours and residual disease Adjuvant chemotherapy may be one of these: Doxorubicin (Q3W) or epirubicin (Q3W) + cyclophosphamide (Q3W) for 4 cycles (12 weeks) followed by paclitaxel (weekly) and carboplatin (weekly or Q3W) for 4 cycles (12 weeks); Doxorubicin (Q3W) or epirubicin (Q3W) + cyclophosphamide (Q3W) for 4 cycles (12 weeks) followed by paclitaxel (weekly) for 4 cycles (12 weeks); Carboplatin (weekly or Q3W) + paclitaxel (weekly) for 4 cycles (12 weeks); Capecitabine (Q3W) for 8 cycles.

Drug: Dato-DXd

Experimental drug IV infusion

Other Names:

Datopotamab deruxtecan (Dato-DXd, DS-1062a)

Drug: Durvalumab

Experimental drug IV Infusion

Other Names:

MEDI4736

Drug: Doxorubicin

IV infusion Experimental/Active Comparator

Drug: Epirubicin

IV Infusion Experimental/Active Comparator

Drug: Cyclophosphamide

IV infusion Experimental/Active Comparator

Drug: Paclitaxel

IV infusion Experimental/Active Comparator

Drug: Carboplatin

IV infusion Experimental/Active Comparator

Drug: Capecitabine

Tablet Oral route of administration Experimental/Active Comparator

Other Names:

XELODA®, Capecitabine Cell Pharm, Capecitabine EG, Capecitabine Accord

Drug: Olaparib

Tablet Oral route of administration Experimental/Active Comparator

Other Names:

LYNPARZA®

Active Comparator: Pembrolizumab plus chemotherapy

Participants receive pembrolizumab every 3 weeks (Q3W) + paclitaxel weekly + carboplatin (weekly or Q3W) x 4 cycles, followed by pembrolizumab Q3W + (doxorubicin OR epirubicin) + cyclophosphamide Q3W x 4 cycles as neoadjuvant therapy prior to surgery; followed by 9 cycles of pembrolizumab Q3W as adjuvant therapy post-surgery. Adjuvant capecitabine (Q3W) for 8 cycles may be given in combination with pembrolizumab only if participants have residual disease. Olaparib may be given for participants with gBRCA-positive tumours and residual disease.

Drug: Pembrolizumab

IV Infusion Active comparator

Other Names:

KEYTRUDA®

Drug: Doxorubicin

IV infusion Experimental/Active Comparator

Drug: Epirubicin

IV Infusion Experimental/Active Comparator

Drug: Cyclophosphamide

IV infusion Experimental/Active Comparator

Drug: Paclitaxel

IV infusion Experimental/Active Comparator

Drug: Carboplatin

IV infusion Experimental/Active Comparator

Drug: Capecitabine

Tablet Oral route of administration Experimental/Active Comparator

Other Names:

XELODA®, Capecitabine Cell Pharm, Capecitabine EG, Capecitabine Accord

Drug: Olaparib

Tablet Oral route of administration Experimental/Active Comparator

Other Names:

LYNPARZA®

Outcome Measures

Primary Outcome Measures

Pathologic Complete Response (pCR) in the experimental vs control arms [At the time of definitive surgery]
pCR rate is defined as the proportion of participants who have no evidence by haematoxylin and eosin staining of residual invasive disease at the time of definitive surgery in the complete resected breast specimen and all sampled regional lymph nodes (ypT0/Tis ypN0) by blinded central evaluation. The analysis will include all randomised participants, as randomised, regardless of whether the participant withdraws from randomised therapy or receives another anticancer therapy. The measure of interest will be the difference between the pCR rates.
Event-free survival (EFS) in the experimental vs control arms [Date of randomization to date of the EFS event, up to 68 months after the first subject randomized]
EFS is defined as the time from the date of randomisation until the date of the first occurrence of any of the following events: disease progression precluding surgery, disease recurrence (local, regional, distant, or contralateral), second primary non-breast invasive cancer (other than squamous or basal cell skin cancer), or death by any cause (in the absence of recurrence). The analysis will include all randomised participants, as randomised, regardless of whether the participant withdraws from randomised therapy or receives another anticancer therapy. The measure of interest will be the Hazard Ratio of EFS.

Secondary Outcome Measures

Overall Survival (OS) in the experimental vs control arms [Date of randomization to date of death due to any cause, up to 82 months after the first subject randomized]
OS is defined as the time from the date of randomisation until the date of death due to any cause. The analysis will include all randomised participants, as randomised, regardless of whether the participant withdraws from randomised therapy or receives another anticancer therapy. The measure of interest will be the Hazard Ratio of OS.
Distant disease-free survival (DDFS) in the experimental vs control arms [Date of randomization to date of the DDFS event, up to 68 months after the first subject randomized]
DDFS is defined as the time from the date of randomisation until the date of the first occurrence of any of the following events: distant metastasis, occurrence of second primary non-breast invasive cancer (other than squamous or basal cell skin cancer), or death by any cause (in the absence of recurrence). The analysis will include all randomised participants, as randomised, regardless of whether the participant withdraws from randomised therapy or receives another anticancer therapy. The measure of interest will be the Hazard Ratio of DDFS.
Participant-reported breast and arm symptoms in the experimental vs. control arms [From Cycle 1 Day 1 of neoadjuvant treatment until pre-surgery safety FU visit (for approximately 24 weeks) or EOT - whichever occurs first.]
Breast and arm symptoms measured by the EORTC IL116. The analysis will include all randomised participants, as randomised, regardless of whether the participant withdraws from randomised therapy or receives another anticancer therapy. The measure of interest is the mean between-arm difference in breast and arm symptom scores.
Participant-reported physical function in the experimental vs. control arms [From Cycle 1 Day 1 of neoadjuvant treatment until pre-surgery safety FU visit (for approximately 24 weeks) or EOT - whichever occurs first, and then from Cycle 1 Day 1 of adjuvant treatment until EOT (for approximately 27 weeks).]
Physical function measured by the PROMIS Physical Function Short Form 8c. The analysis will include all dosed participants. The measure of interest is the mean between-arm difference in physical function scores.
Participant-reported fatigue in the experimental vs. control arms [From Cycle 1 Day 1 of neoadjuvant treatment until pre-surgery safety FU visit (for approximately 24 weeks) or EOT - whichever occurs first, and then from Cycle 1 Day 1 of adjuvant treatment until EOT (for approximately 27 weeks).]
Fatigue measured by the PROMIS Fatigue Short Form 7a. The analysis will include all dosed participants. The measure of interest will be the difference on the proportions of participants reporting different levels of fatigue and mean between-arm difference in the fatigue scores.
Participant-reported Global health status/Quality of life (GHS/QoL)in the experimental vs. control arms [From Cycle 1 Day 1 of neoadjuvant treatment until pre-surgery safety FU visit (for approximately 24 weeks) or EOT - whichever occurs first, and then from Cycle 1 Day 1 of adjuvant treatment until EOT (for approximately 27 weeks).]
Global health status/Quality of life measured by EORTC IL172. The analysis will include all randomised participants, as randomised, regardless of whether the participant withdraws from randomised therapy or receives another anticancer therapy. The measure of interest is the mean between-arm difference in GHS/QoL scores.
Pharmacokinetics of Dato-DXd (in combination with durvalumab) [Day 1 of cycles 1,2,4,8 (Each cycle is 21 days) and at pre-surgery safety follow up visit]
Plasma concentrations of Dato-DXd (ug/ml )
Pharmacokinetics of Dato-DXd (in combination with durvalumab) [Day 1 of cycles 1,2,4,8 (Each cycle is 21 days) and at pre-surgery safety follow up visit]
Plasma concentrations of total anti-TROP2 antibody (ug/ml )
Pharmacokinetics of Dato-DXd (in combination with durvalumab) [Day 1 of cycles 1,2,4,8 (Each cycle is 21 days) and at pre-surgery safety follow up visit]
Plasma concentrations of DXd (MAAA-1181a) (ng/ml)
Immunogenicity of Dato-DXd (in combination with durvalumab) [Day 1 of cycles 1,2,4,8 (Each cycle is 21 days) and at pre-surgery safety follow up visit]
Presence of antidrug antibodies (ADAs) for Dato-DXd (confirmatory results: positive or negative, titres).
Safety of Dato-DXd (in combination with durvalumab) [Randomization to final safety follow-up visit, either 90 days after last dose of study intervention for those who complete planned study intervention or 90 days after date of discontinuation for those who discontinue study intervention prematurely]
Safety and tolerability will be evaluated in terms of AEs graded by CTCAE version 5.0

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Participant must be ≥ 18 years, at the time of signing the ICF.
Histologically confirmed Stage II or III unilateral or bilateral primary invasive TNBC or hormone receptor-low/HER2-negative breast cancer
ECOG PS of 0 or 1
Provision of acceptable tumor sample
Adequate bone marrow reserve and organ function
Contraceptive use by males or females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

Exclusion criteria:

History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 3 years before randomization and of low potential risk for recurrence.
Evidence of distant disease.
Clinically significant corneal disease.
Has active or uncontrolled hepatitis B or C virus infection.
Known HIV infection that is not well controlled.
Uncontrolled infection requiring i.v. antibiotics, antivirals or antifungals; suspected infections; or inability to rule out infections.
Known to have active tuberculosis infection
Resting ECG with clinically significant abnormal findings.
Uncontrolled or significant cardiac disease.
History of non-infectious ILD/pneumonitis
Any prior or concurrent surgery, radiotherapy or systemic anticancer therapy for TNBC or hormone receptor-low/HER2-negative breast cancer
For females only: is pregnant (confirmed with positive serum pregnancy test) or breastfeeding, or planning to become pregnant.
Female participants should refrain from breastfeeding from enrolment throughout the study and for at least 7 months after last dose of study intervention, or as dictated by local PI for SoC if longer.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Jonesboro	Arkansas	United States	72401
2	Research Site	Rogers	Arkansas	United States	72758
3	Research Site	Bakersfield	California	United States	93309
4	Research Site	Los Angeles	California	United States	90095
5	Research Site	Orange	California	United States	92868
6	Research Site	Santa Rosa	California	United States	92805
7	Research Site	Sylmar	California	United States	91342
8	Research Site	Torrance	California	United States	90505
9	Research Site	Aurora	Colorado	United States	80045
10	Research Site	Fort Collins	Colorado	United States	80528
11	Research Site	New Haven	Connecticut	United States	06510
12	Research Site	Newark	Delaware	United States	19713
13	Research Site	Louisville	Kentucky	United States	40202
14	Research Site	Boston	Massachusetts	United States	02215
15	Research Site	Detroit	Michigan	United States	48202
16	Research Site	Grand Rapids	Michigan	United States	49503
17	Research Site	Traverse City	Michigan	United States	49684
18	Research Site	Columbia	Missouri	United States	65212
19	Research Site	Saint Louis	Missouri	United States	63110
20	Research Site	Camden	New Jersey	United States	08103
21	Research Site	Commack	New York	United States	11725
22	Research Site	New York	New York	United States	10065
23	Research Site	Canton	Ohio	United States	44710
24	Research Site	Providence	Rhode Island	United States	02903
25	Research Site	Nashville	Tennessee	United States	37203
26	Research Site	Dallas	Texas	United States	75390-8843
27	Research Site	Tacoma	Washington	United States	98405
28	Research Site	Madison	Wisconsin	United States	53715
29	Research Site	Darlinghurst		Australia	2010
30	Research Site	East Melbourne		Australia	3002
31	Research Site	Waratah		Australia	2298
32	Research Site	Brasschaat		Belgium	2930
33	Research Site	Charleroi		Belgium	6000
34	Research Site	Gent		Belgium	9000
35	Research Site	Leuven		Belgium	3000
36	Research Site	Libramont-Chevigny		Belgium	6800
37	Research Site	Wilrijk		Belgium	2610
38	Research Site	Santo Andre		Brazil	09060-650
39	Research Site	Plovdiv		Bulgaria	4004
40	Research Site	Shumen		Bulgaria	9700
41	Research Site	Sofia		Bulgaria	1330
42	Research Site	Sofia		Bulgaria	1431
43	Research Site	Sofia		Bulgaria	1784
44	Research Site	Sofia		Bulgaria	1797
45	Research Site	Vratza		Bulgaria	3000
46	Research Site	Calgary	Alberta	Canada	T2N 4N2
47	Research Site	Vancouver	British Columbia	Canada	VSZ 4E6
48	Research Site	Barrie	Ontario	Canada	L4M 6M2
49	Research Site	London	Ontario	Canada	N6A 5W9
50	Research Site	Oshawa	Ontario	Canada	L1G 2B9
51	Research Site	Toronto	Ontario	Canada	M5G 2M9
52	Research Site	Levis	Quebec	Canada	G6V 3Z1
53	Research Site	Montreal	Quebec	Canada	H1T 2M4
54	Research Site	Montreal	Quebec	Canada	H2X 0C1
55	Research Site	Montreal	Quebec	Canada	H4A-3J1
56	Research Site	Sherbrooke	Quebec	Canada	J1H 5N4
57	Research Site	St-Jerome	Quebec	Canada	J7Z 5T3
58	Research Site	Chengdu		China	610000
59	Research Site	Hangzhou		China	310009
60	Research Site	Nanchang		China	330009
61	Research Site	Suining		China	629000
62	Research Site	Angers		France	49100
63	Research Site	Avignon		France	84918
64	Research Site	Bayonne		France	64100
65	Research Site	Caen Cedex 5		France	41076
66	Research Site	Clermont Ferrand		France	63011
67	Research Site	Limoges		France	87000
68	Research Site	Lyon		France	69373
69	Research Site	Marseille		France	13273
70	Research Site	Montpellier		France	34298
71	Research Site	Nice		France	06100
72	Research Site	Paris		France	75010
73	Research Site	Reims Cedex		France	51056
74	Research Site	Toulouse		France	31100
75	Research Site	Vandoeuvre les Nancy		France	54519
76	Research Site	Villejuif Cedex		France	94805
77	Research Site	Augsburg		Germany	86150
78	Research Site	Berlin		Germany	10967
79	Research Site	Essen		Germany	45130
80	Research Site	Esslingen am Neckar		Germany	73730
81	Research Site	Frankfurt am Main		Germany	60431
82	Research Site	Freiburg		Germany	79106
83	Research Site	Freiburg		Germany	79110
84	Research Site	Hannover		Germany	30559
85	Research Site	Hannover		Germany	30625
86	Research Site	Heidelberg		Germany	69120
87	Research Site	Mainz		Germany	55131
88	Research Site	Mannheim		Germany	68167
89	Research Site	Münster		Germany	48149
90	Research Site	Hong Kong		Hong Kong
91	Research Site	Budapest		Hungary	1122
92	Research Site	Kecskemét		Hungary	6000
93	Research Site	Miskolc		Hungary	3526
94	Research Site	Nyíregyháza		Hungary	4400
95	Research Site	Salgótarján		Hungary	3100
96	Research Site	Szekszárd		Hungary	7100
97	Research Site	Empoli		Italy	50053
98	Research Site	Lucca		Italy	55100
99	Research Site	Macerata		Italy	62100
100	Research Site	Milano		Italy	20132
101	Research Site	Modena		Italy	41124
102	Research Site	Napoli		Italy	80131
103	Research Site	Padova		Italy	35128
104	Research Site	Roma		Italy	00168
105	Research Site	Rozzano		Italy	20089
106	Research Site	Torino		Italy	10126
107	Research Site	Tricase		Italy	73039
108	Research Site	Udine		Italy	33100
109	Research Site	Daegu		Korea, Republic of	41404
110	Research Site	Goyang-si		Korea, Republic of	10408
111	Research Site	Seongnam		Korea, Republic of	13620
112	Research Site	Seoul		Korea, Republic of	02841
113	Research Site	Seoul		Korea, Republic of	03722
114	Research Site	Seoul		Korea, Republic of	05505
115	Research Site	Seoul		Korea, Republic of	06273
116	Research Site	Seoul		Korea, Republic of	06351
117	Research Site	Seoul		Korea, Republic of	06591
118	Research Site	George Town		Malaysia	10990
119	Research Site	Kuala Lumpur		Malaysia	50586
120	Research Site	Kuala Lumpur		Malaysia	59100
121	Research Site	Kuching		Malaysia	93586
122	Research Site	Selangor		Malaysia	62250
123	Research Site	Singapore		Singapore	168583
124	Research Site	Basel		Switzerland	4031
125	Research Site	Bern		Switzerland	3010
126	Research Site	Rennaz		Switzerland	1847
127	Research Site	Changhua		Taiwan	500
128	Research Site	Kaohsiung		Taiwan	82445
129	Research Site	Taichung		Taiwan	40447
130	Research Site	Tainan		Taiwan	704
131	Research Site	Taipei		Taiwan	10002
132	Research Site	Taipei		Taiwan	10449
133	Research Site	Taipei		Taiwan	112
134	Research Site	Taoyuan		Taiwan	333
135	Research Site	Cardiff		United Kingdom	CF14 2TL
136	Research Site	Edinburgh		United Kingdom	EH1 3EG
137	Research Site	Guildford		United Kingdom
138	Research Site	Lancaster		United Kingdom	LA1 4RP
139	Research Site	London		United Kingdom	EC1A 7BE
140	Research Site	Northampton		United Kingdom	NN1 5BD
141	Research Site	Oxford		United Kingdom	OX3 7LE
142	Research Site	Hanoi		Vietnam	100000
143	Research Site	Ho Chi Minh city		Vietnam	700000